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Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease
G M Hobson1, A P Davis, N C Stowell
1Department of Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19899, USA. ghobson@nemours.org
Background:
Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of the proteolipid protein (PLP) gene are found in most patients.
Objective:
To describe five patients with PMD who have mutations in noncoding regions of the PLP gene.
Methods:
Quantitative multiplex PCR and Southern blot analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene.
Results:
Duplication of the PLP gene was ruled out, and mutations were identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IVS6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 months and progressive spastic ataxia at 18 months was found to have a 19-base pair (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19-bp deletion, are in intron 3, which is involved in PLP/DM20 alternative splice site selection.
Conclusions:
Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.
Insights
Mutations in noncoding regions of the proteolipid protein (PLP) gene cause Pelizaeus-Merzbacher disease (PMD). These intron mutations impact PLP/DM20 alternative splicing, leading to dysmyelination in the central nervous system.
Area of Science:
- Neurogenetics
- Molecular Biology
- Genomics
Background:
- Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive central nervous system (CNS) dysmyelinating disorder.
- Most PMD cases are linked to duplications or point mutations within the coding exons of the proteolipid protein (PLP) gene.
Purpose of the Study:
- To investigate and describe five patients diagnosed with PMD harboring mutations in the noncoding regions of the PLP gene.
Main Methods:
- Quantitative multiplex PCR and Southern blot analyses were employed to identify PLP gene duplications.
- DNA sequencing, encompassing exon-intron boundaries, was utilized to detect mutations within the PLP gene.
Main Results:
- PLP gene duplications were excluded in the studied cohort.
- Mutations were identified in noncoding regions (introns) of the PLP gene in five PMD patients from four families.
- Specific mutations included a G to T transversion at IVS6+3 causing exon 6 skipping, a 19-bp deletion in intron 3 affecting a G-rich region, and two intronic mutations (IVS3+2, IVS3+4) within intron 3, which is crucial for PLP/DM20 alternative splicing.
Conclusions:
- Mutations within the introns of the PLP gene are a significant cause of PMD.
- Even mutations at splice site positions with less than 100% conservation can lead to the disease, highlighting the importance of intronic sequences in proper gene function.
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